Over the past decade the genetics of development and cancer have converged in the identification of signaling pathways that control embryo patterning and, when aberrantly regulated, lead to cancer. Typically, tumors form in tissues in which the pathways normally operate. Tumors arise due to oncogenic mutations in components of these pathways that lead to ligand-independent constitutive activity. A classic example is the canonical Wnt signaling pathway, an essential developmental pathway that is disrupted in several kinds of tumor. Mouse Wnt1 is a prototypical oncogene first identified when it was shown that activation of Wnt1 by integration of Mouse Mammary Tumor Virus led to cancer of the mammary gland in mice. Mutations in several components of the Wnt/beta-catenin pathway have identified both oncogenes and tumor suppressors in this pathway that lead, in particular, to colorectal cancer. Recently, we have shown that aberrant Wnt signaling may lead to cancers of the immune system, specifically T-cell lymphomas. A large-scale survival study has revealed that relatively late-onset lymphomas and thymomas arise in Tcf mutants older than 6 months of age, however when one copy of Wnt5a is removed, severe, early-onset lymphomas arise as early as 3 months of age. These results suggest that Wnt5a has tumor suppressor activity. Our current experiments are aimed at understanding the underlying mechanisms and suggest that Wnt5a normally antagonises the canonical pathway ie. Wnt/beta-catenin target genes such as the proto-oncogene c-myc. We have also initiated a microarray project to generate a transcriptional profile of tumors so that we can molecularly compare our lymphomas with clinically
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